antiallergenic activity.

In addition to the pharmacologic

treatment modalities discussed here,
Improved strategies and new patients with allergic rhinitis may also
treatment options for allergic rhinitis benefit from palliative modes of treat-
ment such as nasal lavage with warm
SANDRA K. WILLSIE, DO salt water (with or without baking soda)
or inhalation of a warm mist through the
nose for 10 to 15 minutes, two to four
times daily.1

Decongestants
Because nasal congestion is one of the
classic yet most problematic symptoms of
Primary principles relevant to the clinical management of allergic rhinitis allergic rhinitis, many patients seek med-
include (1) avoidance of allergens and triggering factors, (2) use of appropriate ications possessing decongestant activity.
pharmacotherapy, (3) evaluation regarding need for and appropriate use of These agents, however, must be used
immunotherapy, and (4) patient education and follow-up. Currently available with caution in certain patient popula-
pharmacotherapeutic options include oral and topical (intranasal) decongestants tions.
and corticosteroids, mast cell stabilizers, intranasal anticholinergics, and anti- Used orally or as nasal sprays,
histamines. Future therapeutic options include leukotriene modifiers and anti- decongestants have sympathomimetic
IgE antibodies. properties that equate to relief of the
(Key words: allergen, allergy, anticholinergics, antihistamines, anti-IgE symptoms of nasal congestion or
antibodies, avoidance, corticosteroids, decongestants, immunotherapy, blockage by constricting blood vessels
leukotriene modifiers, mast cell stabilizers, rhinitis, triggers) in the nasal mucosa.1,4 This constriction
reduces the volume of the edematous
mucosal tissue and eases blockage of the
narrow air passages.1
llergic rhinitis, in addition to having issue that will be discussed in more detail. Oral decongestants include pseu-
A an adverse impact on the patient’s
quality of life, has potentially serious
Essentially, it refers to the idea that treat-
ment should not have side effects that
doephedrine and phenylephrine. Prac-
titioners are cautioned against using these
medical sequelae, including disturbed are worse than the disease itself. Using agents in patients with heart disease,
sleep, exacerbation of asthma, eusta- sedating antihistamines to treat patients hypertension, thyroid disease, diabetes,
chian tube dysfunction with otitis media, with allergic rhinitis, for instance, demon- and urinary difficulties due to prostate
and rhinosinusitis (Figure 1).1,2 strates treatment’s potential to reduce gland enlargement. Side effects of oral
Therefore, the goals of treating cognitive function and performance. decongestants include agitation, dry
patients with allergic rhinitis are control There are four general principles for mucous membranes, exacerbation of thy-
of symptoms while maintaining function clinical management of allergy: rotoxicosis or glaucoma, headache,
and prevention of sequelae—in general,  avoidance of allergens and triggering hypertension (due to nonselective vaso-
improvement of the patient’s quality of factors, constriction), insomnia, restlessness,
life. The control of symptoms “while  use of appropriate pharmacotherapy, tremor, urinary retention, and cardio-
maintaining function” is an important  evaluation of need for immuno- vascular effects such as palpitations,
therapy (allergy vaccine therapy) and tachycardia, and extrasystoles.1
use where appropriate, and Available intranasal or topical
Dr Willsie is vice-dean of academic affairs, admin-  patient education and follow-up.1 decongestants include oxymetazoline
istration, and medical affairs, and professor of hydrochloride, phenylephedrine, and
medicine at the University of Health Sciences–Col-
lege of Osteopathic Medicine in Kansas City, Mo. Pharmacotherapy ephedrine. These agents also relieve nasal
Dr Willsie serves as director of medical education An ideal pharmacologic agent for the obstruction via
-adrenergic–mediated
at the University and as a staff pulmonologist at treatment of patients with allergic vasoconstriction, but, because they are
the University of Health Sciences’ Family Care
Center. rhinitis—and particularly children with applied directly to the nasal mucosa and
This article was developed from Dr Willsie’s this condition—will maintain quality of have limited systemic absorption, they
presentation at Emerging Trends in the Treat- life and meet the following criteria3: act more rapidly and effectively than oral
ment and Management of Allergic Rhinitis, a sym-
posium sponsored by the American College of  proven safety and efficacy, agents and have less potential to cause
Osteopathic Family Physicians and held in San  an easy route of administration with systemic side effects.3
Diego, California on October 24, 2001. rapid absorption, The major limitation to the use of
Correspondence to Sandra K. Willsie, DO, 1750
Independence Ave, Kansas City, MO 64106-1453.  rapid onset of action with no side topical decongestants is development of
E-mail: swillsie@uhs.edu effects, and rhinitis medicamentosa. This condition is

Willsie • Improved strategies and new treatment options for allergic rhinitis JAOA • Supplement 2 • Vol 102 • No 6 • June 2002 • S7

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Allergic conjunctivitis
Sinusitis
Otitis media
Asthma
Figure 1. Other conditions associated with allergic rhinitis because of common passageways.
(Sources: LifeART. Copyright © 2001 Lippincott Williams & Wilkins, and American Academy of
Allergy, Asthma, & Immunology. The Allergy Report. Available at: http://www.theallergy
report.org/ reportindex.html. Accessed April 2, 2002.)
a rebound phenomenon that causes an
increase in nasal congestion and edema,1,5
which can result from several days of
continual use. Therefore, the use of top-
ical decongestants should be limited to 3
to 5 days, and it is probably best to be
more cautious and limit the use to no
more than 3 days. Both adults and chil-
dren, but especially children, may be sus-
ceptible to an intoxication phenomenon,
which is another reason to be cautious
in using these drugs. This intoxication
phenomenon, seen particularly with the
imidazoline derivatives (eg, naphazoline
hydrochloride)6 may manifest itself in
children and infants as severe central
nervous system (CNS) depression or as
cardiovascular side effects.3
An appropriate short-term use of
topical nasal decongestants is for severe
airflow obstruction or blockage to “clear
the way” for other topical nasal medica-
tions (eg, intranasal steroids) to reach the
Allergic
rhinitis
nasal mucosa. When rhinitis medica-
mentosa occurs secondary to the use of
topical decongestants, use of the decon-
gestant should be discontinued and nasal
corticosteroid therapy initiated. In severe
cases, a short course of oral corticoste-
roid therapy might be necessary.1
Intranasal corticosteroids
The development of intranasal steroids
revolutionized the treatment of allergic
rhinitis. These agents are judged to be
most efficacious in alleviating the symp-
toms of allergic rhinitis, treating the
underlying inflammatory disease pro-
cess in the nasal mucosa.7 Essentially,
antihistamines treat the early-phase reac-
tion caused by immediate release of
inflammatory mediators, including his-
tamine, on exposure to allergen.1 In con-
trast, repeated dosing of intranasal corti-
costeroids treats not only the early-phase
response but also the late-phase allergic
inflammatory reaction caused by infil-
tration of the nasal mucosa with acti-
vated immune cells such as eosinophils
and lymphocytes. These agents also
reduce endothelial and epithelial per-
meability, increase sympathetic vascular
tone, decrease the response of mucous
glands to cholinergic stimulation, and
reduce nasal hyperreactivity.7
Corticosteroids, which include
beclomethasone, budesonide, flunisolide,
fluticasone propionate, mometasone, and
triamcinolone, are considered first-line
therapy for patients with predominant
nasal obstruction.1
Onset of action may be 4 to 12 hours
after the first dose, with a maximal ther-
apeutic effect typically achieved only
after regular use for days or weeks.1,7
Because corticosteroids target the under-
lying inflammatory disease process
rather than providing immediate
symptom relief, they must be taken on a
regular basis—even when symptoms are
absent—to preserve their effectiveness.
Ideally, once the therapeutic effect has
been achieved, dosing of the cortico-
steroid should be tapered to the lowest
effective dose for maintenance therapy.
Corticosteroids can be given concurrently
with antihistamines to patients who con-
tinue to have nasal and/or ocular symp-
toms.1
Local side effects of intranasal corti-
costeroids include burning, dryness, epis-
taxis (nosebleed), sneezing, and stinging.1
Although these agents clearly have fewer
systemic effects than oral corticosteroids,
clinicians and parents may still associate
steroid use with possible growth retar-
dation in children, particularly when
these drugs are taken long term.4 Overall,
these agents are considered to be safe
and effective when used at recom-
mended doses. Although some short-
term studies have suggested that
intranasal corticosteroids cause a reduc-
tion in growth velocity in children,8-10 it
is not clear whether a child’s ultimate
height is affected by corticosteroid use
or if some phases of growth are merely
suppressed temporarily. In several
longer-term studies, although growth
rates were reduced during the first years
of treatment with intranasal corticoste-
roid, subjects ultimately attained normal
adult height.11-13

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ANTIHISTAMINES
Second generation
Terfenadine hydrochloride
Astemizole
Loratadine
Cetirizine hydrochloride
Use of topical corticosteroids pro-
phylactically before seasonal allergen
exposure has been shown to delay onset
of symptoms and may reduce the need
for higher-dose therapy when pollen
season begins.14 Specifically, nasal corti-
costeroid therapy should begin 10 to 14
days before the beginning of the allergen
season or at the onset of symptoms, and
it should continue for 2 to 3 weeks after
the end of the season to reduce nasal
hyperreactivity, which may persist after
allergen exposure has ended.1
Mast cell stabilizers
Cromolyn sodium can be quite effective
in some patients with allergic rhinitis.
Although the exact mechanism of action
is unclear, it is hypothesized that cro-
molyn inhibits the release of histamine
and other inflammatory mediators by
stabilizing mast cells.15
Intranasal cromolyn, available over
the counter, is a topical nonsteroidal anti-
inflammatory agent that blocks both
early- and late-phase allergic responses.
It relieves sneezing, rhinorrhea, nasal
congestion, and nasal itching, but not
ocular symptoms. It has an excellent
safety profile; the most common side
Willsie • Improved strategies and new treatment options for allergic rhinitis
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Next generation
Fexofenadine hydrochloride
Tecastemizole (investigational)
Desloratadine
Levocetirizine (investigational)
effects are local: sneezing and nasal
burning.1
Overall, cromolyn is not as effective
as the nonsedating oral antihistamines
or topical nasal corticosteroids; for max-
imal efficacy, it should be given pro-
phylactically, before the onset of symp-
toms.16 The drug is most effective when
started before an anticipated allergen
exposure and when given 4 to 6 times
daily, which is a regimen that can be dif-
ficult to maintain consistently.1
Intranasal anticholinergics
Anticholinergics such as ipratropium
bromide inhibit the effects of acetyl-
choline by blocking its binding to recep-
tors at neuroeffector sites on glandular
tissue, thereby reducing the amount of
watery rhinorrhea in patients with
allergic and nonallergic rhinitis.17-19
Although safe and effective in reducing
rhinitis-induced hypersecretion, the agent
does not relieve nasal congestion, itching,
or sneezing. This agent is also not well
absorbed from the nasal mucosa and, as
such, side effects are local and may
include nasal dryness and a bloody nasal
discharge. The side effects are dose
related.1
JAOA • Supplement 2 • Vol 102 • No 6 • June 2002 • S9
 Figure 2. Development of next-generation
antihistamines. (Source: Handley DA.
Advancement of the third generation of anti-
histamines. Pediatr Asthma Allergy Immunol.
1999;13:163-168.)
Antihistamines
Antihistamines remain the mainstay of
pharmacotherapy for allergic rhinitis.1
They are histamine receptor type 1 (H1)
antagonists and block the histamine-
induced symptoms of allergic rhinitis:
rhinorrhea, itching, and sneezing, as well
as related symptoms in the eyes and
throat. Generally, antihistamines are not
considered effective for treating nasal
congestion.
 First-generation antihistamines—
The first-generation antihistamines (eg,
chlorpheniramine, diphenhydramine,
tripelennamine, and clemastine fumarate)
are effective H1-receptor antagonists.
Problems associated with their use relate
to side effects, which are numerous and
can be severe in some patients. The most
common and most important side effects
are anticholinergic, including dry mouth
and eyes, urinary retention, and CNS
effects, primarily sedation/drowsiness,
and impairment of motor and cognitive
functions.20 Anticholinergic effects may
be particularly serious, for example, in
older individuals or in men with preex-
isting urinary retention secondary to
prostate enlargement; the elderly may
also be more susceptible to sedation and
cognitive and motor impairment caused
by these drugs.20
Central nervous system side effects
can be problematic in any patient, par-
ticularly those who need to drive motor
vehicles or operate complex machinery,
or pay attention and learn in school.
Often underrecognized are the potenti-
ating effects of alcohol and other CNS-
depressing drugs such as sedatives, hyp-
notics, and antidepressants.20 First-
generation antihistamines are available
over the counter and are generally inex-
pensive; therefore, patients often take
these agents without consulting their care
provider—preferring instead to take
them rather than more costly but nonse-
dating antihistamines that are available
by prescription only (see following dis-
cussion).
 Figure 3. Possible effect of allergen
immunotherapy on immune response to
allergen exposure: a shift from helper T cells
type 2 (TH2) lymphocytes, which predomi-
nate in allergic individuals, to helper T cells
type 1 (TH1) lymphocytes. (Modified from
Hedlin G. The role of immunotherapy in pedi-
atric allergic disease. Curr Opin Pediatr.
1995;7:676-682.)

Side effects of first-generation anti-
histamines are based on two phenomena:
(1) they have poor specificity for the H1
receptor and therefore interact with other
receptors such as the cholinergic receptor,
and (2) they readily cross the blood-brain
barrier and interact with various recep-
tors in the CNS.20
These problems were largely
resolved when second-generation anti-
histamines became available. These
agents have good specificity for the H1
receptor and as the result of structural
modifications, do not readily cross the
blood-brain barrier.21
 Second-generation antihistamines—
The earliest second-generation antihis-
tamine was terfenadine, followed by
astemizole and loratadine. These agents
are classified as nonsedating because
their tendency to cause sedation is no
greater than that of placebo. Cetirizine
hydrochloride causes significantly less
sedation than most first-generation anti-
histamines but more than the nonse-
dating second-generation agents.22
After years of use, attention focused
on reports of terfenadine and astemizole
causing prolongation of the QT interval
on electrocardiogram—albeit in rare
cases, and primarily at elevated tissue
levels. 23-26 Prolongation of the QT
interval, which reflects delayed myocar-
dial repolarization, can increase the risk
for development of potentially lethal ven-
tricular tachyarrhythmias, or torsades de
pointes.22,27 Torsades de pointes typically
developed in individuals who were
taking concomitant erythromycin or keto-
conazole.
As a result of their causing
arrhythmia, terfenadine and astemizole
have been withdrawn from the market in
the United States. There is no associa-
tion of cetirizine and loratadine with sim-
ilar cardiac effects.
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TH 2
Antigen Immunotherapy
TH 1
 “Next-generation” antihistamines—
Reports of cardiac toxicity related to ter-
fenadine and astemizole provided the
impetus for development of “next-gen-
eration” antihistamines. Next-generation
antihistamines are typically the struc-
turally modified, active metabolites or
isomers of second-generation antihis-
tamines (Figure 2). These agents retain
the nonsedating properties of second-
generation antihistamines21 while elimi-
nating or limiting the cardiac risks that
are associated with some of the second-
generation antihistamines.28
Fexofenadine, an active metabolite
of terfenadine that does not cause QT
prolongation,29 was approved for mar-
keting in the United States in 1996. This
agent, like terfenadine, has no associated
CNS or anticholinergic side effects and
undergoes little or no hepatic metabo-
lism. There has been a single case report
of a patient receiving fexofenadine
hydrochloride in whom cardiac arrhyth-
mias developed; however, because this
patient had numerous predisposing fac-
tors for cardiac dysrhythmias, no causal
effect was established.30 Indicated for the
relief of symptoms associated with sea-
sonal allergic rhinitis in adults and chil-
dren 6 years of age and older, the agent
effectively treats sneezing, rhinorrhea,
itchy nose/palate/throat, and itchy/
watery/red eyes.31
In a 14-day, multicenter, placebo-
controlled, double-blind trial to investi-
gate the clinical efficacy and safety of fex-
ofenadine in the treatment of ragweed
Willsie • Improved strategies and new treatment options for allergic rhinitis
IL-4 IgE

Late-phase reaction

IFN- IgG
seasonal allergic rhinitis, patients received
fexofenadine hydrochloride (60 mg,
120 mg, or 240 mg twice a day) or
placebo at 12-hour dosing intervals
(N 570).32 At each dosage, fexofena-
dine provided significant improvement
in total symptom score (P  .003) and
in all individual nasal symptoms com-
pared with placebo. The frequency of
adverse events was similar among fex-
ofenadine-treated and placebo groups,
and no dose-related trends were
observed. In addition, no sedative effects
or electrocardiographic abnormalities—
including prolongations in QT inter-
vals—were detected.
Desloratadine, an active metabolite
of loratadine, was recently approved for
marketing in the United States. Indicated
for the relief of the nasal and nonnasal
symptoms of seasonal and perennial
allergic rhinitis in patients 12 years of
age and older, desloratadine is a long-
acting tricyclic histamine antagonist with
selective H1-receptor histamine antago-
nist activity.33 Like loratadine, deslo-
ratadine is nonsedating and has not
demonstrated clinically relevant cardiac
effects. Clinical experience in more than
2300 patients has shown the adverse
event profile of desloratadine to be sim-
ilar to that of placebo. In addition, the
agent does not impair wakefulness, psy-
chomotor function, or driving perfor-
mance, and it does not exacerbate the
effects of alcohol.20,34
Tecastemizole, previously known
as norastemizole, is a primary active

ALLERGEN IMMUNOTHERAPY
 Patient selection:
Adequate screening
 Presence of IgE-mediated
disease
 Disease severity and symptom
assessment
 Ability to avoid exposure to
allergen(s)
 Effectiveness of
pharmacotherapy
 Comparative cost and
duration of treatment
modalities
 Assessment of overall risk
 Quality and availability of
allergen extract
 Identification of specific
allergens through skin testing
Figure 4. Issues in patient selection for immunotherapy (allergen injection therapy). (Source:
DuBuske LM. Appropriate and inappropriate use of immunotherapy. Ann Allergy Asthma
Immunol. 2001;87(1 suppl 1):56-67.)
metabolite of astemizole. A potent, once-
daily, nonsedating antihistamine,
tecastemizole has shown approximately
13 times more potent binding affinity for
H1 receptors than astemizole35 and has an
enhanced pharmacokinetic profile.
Specifically, it has a faster onset of action,
it undergoes little or no hepatic metabo-
lism, and it appears to have no effect on
cardiac rhythm.36
Levocetirizine, the active enantiomer
(stereoisomer) of cetirizine, is currently
approved in Europe and is in clinical
development in the United States. In a
recently published study of healthy male
subjects, levocetirizine was found to be
more potent and consistent than other
commonly prescribed H1 antihistamines
(ebastine, fexofenadine, loratadine, and
mizolastine) for blocking the cutaneous
response to histamine.37 In a random-
ized, double-blind, four-way, crossover
study, Wang et al38 assessed the effect of
treatment with levocetirizine (5 mg), dex-
trocetirizine (5 mg) and cetirizine
Willsie • Improved strategies and new treatment options for allergic rhinitis
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 Safety considerations:
Relative contraindications
 Age younger than 5 years
 Significant immunodeficiency
or severe disease
 Highly allergic individuals
 Uncontrolled asthma and/or
asthma associated with
irreversible airway obstruction
 Poor compliance
hydrochloride (10 mg), and matched
placebo on histamine-induced changes
in the nasal airways of 24 healthy sub-
jects.38 Following nasal aerosol challenge
with increasing concentrations of his-
tamine in both nostrils, the histamine
threshold concentration was increased
by fourfold (from 8 mg/mL to
32 mg/mL) after treatment with ceti-
rizine (P  .05) or levocetirizine
(P  .025). In addition, treatment with
either cetirizine or levocetirizine signifi-
cantly reduced histamine-induced
sneezes compared with placebo (P  .01).
To receive approval of the Food and
Drug Administration, these agents must
demonstrate equivalent or better efficacy,
greater safety (ie, absolutely no adverse
cardiac effects), and improved conve-
nience (such as once-daily dosing or
faster onset of action) than the previous
generation of antihistamines.
Leukotriene modifiers
As part of the early-phase allergic
JAOA • Supplement 2 • Vol 102 • No 6 • June 2002 • S11
response, arachidonic acid is released
from cell membrane phospholipids and
converted to the eicosanoids: leuko-
trienes, prostaglandins, and thrombox-
anes. The cyclooxygenase pathway of
arachidonic acid metabolism yields
prostaglandins and thromboxanes; the
5-lipoxygenase pathway produces
leukotrienes, four of which have proin-
flammatory effects: leukotriene B4 (LTB4),
LTC4, LTD4, and LTE4. The latter three,
LTC4, LTD4, and LTE4, each contain a
cysteine amino acid residue and are
therefore known as the cysteinyl
leukotrienes.39
Leukotriene modifiers include an
inhibitor of the 5-lipoxygenase enzyme
(zileuton) and three cysteinyl leukotriene
receptor antagonists: pranlukast (inves-
tigational), zafirlukast, and montelukast,
each of which inhibits bronchoconstric-
tion.40,41 These agents are indicated for
the treatment of asthma, but they may
also have potential value for the treat-
ment of allergic rhinitis and are being
investigated for this purpose. In clinical
studies, zileuton,42 zafirlukast,43 and
pranlukast have demonstrated efficacy
in reducing symptoms of allergic
rhinitis.44,45
Recently, the results of a random-
ized, double-blind, placebo-controlled,
clinical trial demonstrated the efficacy of
combination therapy with montelukast
and loratadine in patients with seasonal
allergic rhinitis.46 In the study, 460 men
and women aged 15 to 75 years with sea-
sonal allergic rhinitis were randomly
assigned to receive one of the following
regimens for 2 weeks, once daily in the
evening: montelukast, 10 mg or 20 mg;
loratadine, 10 mg; montelukast, 10 mg,
plus loratadine, 10 mg; or placebo. The
results showed that the combination
therapy significantly improved daytime
nasal symptoms scores (P  .001), com-
pared with placebo and each agent alone.
The combination treatment also signifi-
cantly improved eye symptoms, night-
time symptoms, results of global evalu-
ations, and quality of life, and was well
tolerated, with a safety profile compa-
rable to that of placebo.
Allergen immunotherapy
In 1911, Noon47 first published his system
for prophylactic inoculation against hay
 Figure 5. Effects of IgE in the early- and late-
phase allergic reactions, which may be
reduced or blocked by anti-IgE therapy.
(Source: National Asthma Education and Pre-
vention Program. Expert Panel Report 2:
Guidelines for the Diagnosis and Manage-
ment of Asthma. Bethesda, Md: National
Institutes of Health; 1997. NIH Publication
No. 97-4051.)
fever, and, since then, allergen im-
munotherapy has been used for the treat-
ment of patients with allergic diseases.
This process involves administering
repeated doses of allergen-containing
substances to the patient with the goal
of altering the immune system’s
responses, ie, desensitizing the patient
to those allergens and reducing symp-
toms triggered by subsequent expo-
sures.48 In patients with seasonal allergic
rhinitis, immunotherapy blunts the sea-
sonal rise in specific immunoglobulin
(IgE) antibody levels.
The allergen extract is given in
increasing doses, and protocols may vary
considerably. These regimens range from
“rush” protocols—in which injections are
given several times a day—to relaxed
schedules that may last months, a year, or
more. In such long-term scenarios, injec-
tions might be given once or twice weekly
or once every several weeks. Immu-
noglobulin G antibodies to the antigen
are produced, which is considered a sign
that the treatment is eliciting a response.
However, although the IgG antibodies
may participate in the desensitization pro-
cess, possibly by competing with IgE for
binding of the allergen, many immuno-
logic changes occur with immunotherapy
that do not involve IgG.48 Allergy vac-
cine is thought to work, at least in part, by
shifting the allergic response from helper
T cells type 2 (TH2) lymphocytes, which
predominate in allergic individuals, to
helper T cells type 1 (TH1) lymphocytes
(Figure 3).49 In a randomized, double-
blind, placebo-controlled trial assessing
the long-term efficacy of immunotherapy
for grass-pollen allergy, investigators
reported that immunotherapy for 3 to 4
years continued to reduce symptoms and
the need for rescue medication for 3
years after discontinuing immuno-
therapy injections.50
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MAST CELL
Proinflammatory
cytokines, Il-4
Histamine
Leukotrienes

IL-8
Tryptase
Chemokines LTB4
BRONCHOSPASM
NEUTROPHILS
Acute
The efficacy of immunotherapy in
allergic rhinitis has been demonstrated in
a number of studies involving tree, grass,
and ragweed pollens; dust mites and
molds; and cat allergens.48 The main risk
of immunotherapy is the possibility of a
local or systemic reaction, including, in
the worst case, a life-threatening or fatal
reaction (anaphylaxis). In a prospective
safety study of 419 patients receiving bio-
logically standardized extracts, local reac-
tions occurred in 10.5% of patients, and
systemic reactions in 4.8% of patients;
0.37% of the total 9482 injections given
were associated with systemic reactions.51
In a 10-year review of immunotherapy at
the Mayo Clinic, there were 109 systemic
reactions among 79,593 injections (a rate
of 0.137%), two instances of hypotension,
and no fatalities.52 The risk of a systemic
reaction is greater during “rush” im-
munotherapy, in which escalating injec-
tions may be given several times a day.48
The key issue in immunotherapy is
careful and appropriate selection of
patients (Figure 4), and documentation
of symptomatic allergen sensitivity asso-
ciated with symptoms is essential before
treatment is initiated. In addition, symp-
toms should be of sufficient duration and
severity to warrant immunotherapy.53
After a thorough history is taken and a
physical examination is conducted, each
patient must undergo allergy testing.48
Anti-IgE antibody therapy
As the early-phase allergic reaction in
the respiratory tract mucosa is triggered
Willsie • Improved strategies and new treatment options for allergic rhinitis
ANTIGEN
IgE
MACROPHAGES
T Cell B Cell
IL-5
IL-5 Proinflammatory
cytokines
EOSINOPHIL
Cytokines
Activated MACROPHAGES
INFLAMMATION
Subacute Chronic
when allergens bind to IgE antibodies
that are bound to receptors on immune
cell surfaces, resulting in degranulation
and other activation processes, it is log-
ical to assume that blocking the binding
of IgE to immune cell surface receptors
would block the allergic response. An
anti-IgE antibody inhibits production of
IgE in B lymphocytes, neutralizes circu-
lating IgE antibodies by binding to them,
and prevents IgE antibodies from
attaching to immune cell surface recep-
tors.54 Figure 5 shows the cellular mech-
anisms involved in airway inflammation
and the effects of allergen-bound IgE in
the early- and late-phase allergic
responses, all of which may be reduced
by blockade of IgE-mediated degranu-
lation and activation of immune cells.55
A recombinant humanized murine
(mouse) monoclonal antibody, omal-
izumab, has been shown in a random-
ized clinical trial to reduce nasal
symptom scores in patients with sea-
sonal ragweed allergic rhinitis.56 In this
double-blind trial, 536 patients aged 12 to
75 years were randomly assigned to
receive one of three doses of omal-
izumab, or placebo subcutaneously just
before the ragweed pollen season and
every 3 or 4 weeks (depending on the
patients’ IgE levels) for a total of three
or four treatments. Nasal symptom
severity scores in patients who received
the highest dose of omalizumab (300 mg)
were significantly lower than in those
who received placebo (P  .002), and IgE
reduction appeared to correlate with

Checklist
 Oral decongestants
(Provide no benefit for sneezing,
itching, and rhinorrhea; provide
modest benefit in relieving
congestion.)
 Pseudoephedrine
 Phenylephrine
 Intranasal/topical decongestants
(Provide no benefit for sneezing,
itching, and rhinorrhea; provide sub-
stantial benefit for congestion.)
 Oxymetazoline hydrochloride
 Phenylephedrine
 Ephedrine
 Intranasal corticosteroids
(Provide substantial benefit in relieving
sneezing, itching, congestion, and rhi-
norrhea.)
 Beclomethasone
 Budesonide
 Flunisolide
 Fluticasone propionate
 Momentasone
 Triamcinolone
 Intranasal mast cell stabilizers
(Provide modest benefit in relieving
sneezing, itching, congestion, and
rhinorrhea.)
 Cromolyn sodium
 Intranasal/topical anticholinergics
(Provide substantial benefit in relieving
rhinorrhea; no benefit in relieving
sneezing, itching, and congestion.)
 Ipratropium bromide
lower use of rescue antihistamine
therapy. The treatment was well toler-
ated, with similar rates of adverse events
in the groups receiving the active treat-
ment and the group receiving placebo.
Comment
The ideal approach to treatment of
patients with allergic rhinitis will be indi-
vidualized, with attention given to the
identification and avoidance of triggers in
all cases. Responsible practitioners will
evaluate the benefit-risk ratio for available
agents (Figure 6) before deciding what
to prescribe for their patients. Mainstay
therapeutic agents that have been proven
effective in treating patients with allergic
rhinitis—particularly when nasal obstruc-
tion plays a role—include the topical,
Willsie • Improved strategies and new treatment options for allergic rhinitis
Downloaded from https://jaoa.org by guest on 05/05/2019
 Antihistamines
(Oral formulations provide substantial
benefit in relieving sneezing, itching,
and rhinorrhea and minimal benefit in
relieving congestion. Intranasal formu-
lations provide moderate benefit in
relieving sneezing, itching, and rhinor-
rhea and minimal benefit in relieving
congestion.)
 First generation
(Side effects may be prohibitive.)
— chlorpheniramine
— diphenhydramine
— tripelennamine
— clemastine fumarate
 Second generation
(Nonsedating)
— terfenadine*
— astemizole*
— loratadine
— cetirizine hydrochloride
 Next generation
(Nonsedating)
— fexofenadine hydrochloride
— desloratadine
— tecastemizole (investigational)
— levocetirizine (investigational)
 Leukotriene modifiers
(Indicated for the treatment of asthma,
these agents are being investigated for
efficacy in reducing the symptoms of
allergic rhinitis.)
 Zileuton
 Pranlukast (available in Japan)
 Zafirlukast
 Montelukast sodium
*Not available in United States because of
prolonged QT interval.
intranasal corticosteroids. Other avail-
able agents with proven efficacy include
leukotriene modifiers, which are gener-
ally considered to be well tolerated, effec-
tive in reducing nasal congestion, and,
like intranasal corticosteroids, probably
work best when combined with an anti-
histamine.
A variety of new pharmacologic
agents are now available for the treat-
ment of patients with allergic rhinitis
(Figure 6). These include a number of
next-generation antihistamines that pro-
vide the benefit of incrementally
improved potency, quicker onset of
action, and longer duration of action,
without evidence of clinically significant
cardiac toxicity. In addition, consideration
should be given to the use of allergen
JAOA • Supplement 2 • Vol 102 • No 6 • June 2002 • S13
 Figure 6. Pharmacologic agents available
and in clinical trials for the treatment of
patients with allergic rhinitis and their effec-
tiveness in relieving specific symptoms.
immunotherapy in selected pediatric
cases in which early experimental evi-
dence suggests that control of allergic
rhinitis may help prevent the develop-
ment of asthma. Finally, although fur-
ther studies are indicated and the poten-
tial cost of this therapy may limit its
clinical usefulness in some patients, the
use of anti-IgE therapy may offer poten-
tial benefit for certain individuals with
allergic rhinitis by downregulating
allergic and inflammatory responses.
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